1. Field of the Invention
This invention relates to processes for making polymer conjugates of therapeutic, agricultural, and food additive compounds. More specifically, the invention relates to processes employing “Mitsunobu” reaction conditions to prepare conjugates for use in treating various mammalian, particularly human, diseases and disorders as well as in agriculture and as food additives. In certain aspects, the invention relates to using “Mitsunobu” conditions with an alcohol, particularly a primary or secondary alcohol-containing active compound, and a polymeric nucleophile to form the desired conjugates.
2. Description of the Related Art
Attachment of biologically active compounds to polymers has received significant attention and has become a common method to control various characteristics, e.g., biodistribution, pharmacokinetics, and toxicity, of such compounds. A frequent choice of polymer for use in making polymer conjugates of biologically active compounds is polyethylene glycol (PEG). It is widely used as a covalent modifier of both small and large biologically active molecules. For discussions of such conjugates, see, Eur. Polym. J. 19, No. 12, pages. 1177-1183 (Zaplinsky et al., 1983) et al., Journal of Controlled Release 10 (1989) 145-154 (Veronese et al., 1989), and Advanced Drug Delivery Reviews, 16, 157-182 (Zaplinsky, 1995).
It has recently been discovered that polymer conjugates of, for example, α4β1 (VLA-4) antagonists have greatly improved serum half-life. These polymer compounds can be prepared using various synthetic methods, including carboxamide formation by reaction of an ester of the active molecule with a polymer amine, carbamate formation between an amine of the active molecule and a polymer chloroformate, or carbamate formation between an isocyanate of the active molecule and a polymer alcohol. The overall yields from these methods are typically less than desirable, often involving multiple steps and purification means. It is therefore necessary to design a process which isolates a conjugate of a VLA-4 inhibitor in quantitative or near quantitative yields.
The importance of such polymer conjugates indicates that there is a need for convenient and efficient syntheses of such materials.